The general aim of this proposal is to understand at a biochemical level, the regulatory mechanisms which control characteristic functions (the oxidative burst, secretion/degranulation chemotaxis) of human polymorphonuclear leukocytes (PMN). Initial studies will focus on two observations: First, sphingoid long-chain bases (sphinganine and sphingosine) block the oxidative burst and modulate secretion patterns, apparently by specifically inhibiting protein kinase C. Preliminary evidence suggests that long-chain bases may be mobilized physiologically, and may therefore function as endogenous negative effectors of PK-C. These compounds may function as endogenous anti-inflamatory molecules and/or "anti-timor promotors," and may provide a new mode of intervention in chronic inflamatory diseases (e.g. rheumatoid arthritis, shocklung, etc.) Second, oncogene-related growth factors (e.g. platelet-derived growth factor and epidermal growth factor) rapidly modulate the response (oxidative burst) of PMN to the activator peptide formyl-met-leu-phe, demonstrating interconnections among growth factor-regulated and other receptor-linked regulatory processes. Proposed studies may provide a model for interpreting early events related to some oncogene products and their normal cellular counterparts. Techniques to be used include autoradiography, SDS gel electrophoresis, spectrophotometry, HPLC, subcellular fractionation, scintillation counting, fluorescence, and various kinetic approaches.